Opportunities for Addressing Unmet Clinical Need in Brain Cancer Colin Watts cw209@cam.ac.uk

Brain Cancer has a disproportionate burden of disease on the individual that is poorly recognised Brain Cancer accounts for 2% of cancers but 7% of cancer deaths Astrocytic tumours are the third leading cause of cancer related death in middle aged men Astrocytic tumours are the fourth leading cause of death among women aged 15-34

Glioblastoma is biologically complex at presentation

So how can we develop multimodal precision therapeutics?

We can interrogate spatial and temporal intratumour heterogeneity in patients in real time to establish a biological rationale for drug targeting Figure 5. Reconstruction of GB progression. The combination of sampling information, copy number and gene expression profiles, and molecular clock data enable the reconstruction of tumor progression, as shown here for SP42. The evolution of the malignancy is illustrated by the accumulation of CNAs in different parts of the tumor and the corresponding variation in the gene expression profile, which reveals that T4 is classified as a different subtype (mesenchymal) with respect to the rest of the neoplasm (proneural). Moreover, we report the presence of variable numbers of sub-clones in each tumor fragment.

We can develop a patient-derived xenogeneic platform for high-throughput screening & technology development

An example of multimodal therapeutics through nanotechnology Setua et al 2014 Nanoscale 6 (18) 10685-73

Aim of the project Development of peptide functionalized drug-gold nanoparticle conjugate for targeted chemoradiotherapy of GBM (We use patient derived GBM cells) As an alternative we proposed to develop peptide functionalized drug-gold nanoparticle conjuagte for cancer cell targeted chemoradiotherapy of GBM. Schematic showing how the proposed nanosystem will work : the nanomedicine will be made of gold nanoparticle surface functionalized with anti-cancer drug cisplatin. MUA (mercaptoundecanoic acid ) works as a linker between drug and the gold nanoparticle. After entering in the cancer cell by endocytosis, cisplatin will be released from the gold nanoparticle due to the acidic pH of the late endosome. Free ciplatin will bind with the guanine of the DNA resulting in intrastrand and interstarnd DNA cross-link. This cross links will initiate DNA damage. In presence of radiation, gold nanoparticles and platinum of the drug will emit ionizing photoelectron and Auger electrons (because of photoelectric effect, high atomic number of gold and platinum help in this process). These electrons will ionize the water inside cells and will produce large amount of reactive oxygen species (ROS). ROS will further damage the DNA and cellular proteins. These will kill the cancer cell. (MUA) AuNP: Gold nanoparticle

Radiosensitizing potential of AuNP Control + RT AuNP-HSA + RT AuNP-PEI + RT Growth Curve : GBM cell line GBM xenograft model P = 0.0486 Control Next we checked the radiosensitizing capacity of the conjugate by DNA damage (yH2AX) assay, Apoptosis (Caspase-3) assay and growth curve. (representative image and quantification of the signals) We found increased DNA damage and higher caspase 3 activation in case of AuNP-PEI. This initiated higher cell death in growth curve. However, the cells could recover from the damage. In vivo result also shows that the survival of the AuNP-PEI group is not significantly higher than the control. So, gold nanoparticle mediated radiosensitization is not a effective therapy for these patient derived GBM cells. Control + RT AuNP-PEI AuNP-PEI + RT * = P < 0.05, ** = P < 0.01, *** = P < 0.001 AuNP + RT can not decrease the growth of GBM cells effectively.

Radiosensitizing potential of AuNP-Pt Control+RT AuNP-MUA+ RT AuNP-Pt + RT * = P < 0.05 *** = P < 0.001 In presence of radiation excellent synergy of cisplatin mediated chemotherapy and gold + platinum (of cisplatin) mediated radiosensitization was found AuNP-Pt + RT can decrease the growth of GBM cells significantly.

What do we need? Targeted delivery specifically to tumour cells Capacity to deliver multiple drug payloads Maximise therapeutic efficacy Minimise toxicity associated with combinatorial therapeutics Local and systemic therapies Real-time diagnostics that can control for biological heterogeneity

How can we do this? cw209@cam.ac.uk Strategies for tumour-cell targeting Linking biology & technology Developing a (nano)technology platform High-throughput evaluation using validated biological platforms In silico modelling Tunable adaptive technology to deliver precison therapeutics cw209@cam.ac.uk